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Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis.

Koerner-Rettberg C, Doths S, Stroet A, Schwarze J - PLoS ONE (2008)

Bottom Line: Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response.In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Ruhr University of Bochum, Bochum, Germany.

ABSTRACT

Background: In asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.

Methodology/principal findings: Mice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-beta)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.

Conclusions: Prolonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

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Eosinophils and lymphocytes in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, numbers of (a) eosinophils, and (b) lymphocytes were determined in BAL fluid from 3 days to 8 weeks after final airway challenge, n≥12 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0,05, **/++ p<0,01, ***/+++ p<0,001.
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pone-0001575-g003: Eosinophils and lymphocytes in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, numbers of (a) eosinophils, and (b) lymphocytes were determined in BAL fluid from 3 days to 8 weeks after final airway challenge, n≥12 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0,05, **/++ p<0,01, ***/+++ p<0,001.

Mentions: To characterise the quality of airway inflammation, BAL cells were analysed. 72 hours after the final challenge total cell numbers in BAL fluid were raised 6–10 fold compared to control mice without significant differences between the two challenge protocols (PBS: 124,900±18,300 cells/ml, short term OVA: *1,081,100±244,900, long term OVA: *841,800±90,200, *p<0.05 versus PBS, n≥10). BAL cell numbers remained significantly elevated (3-fold over controls) until 8 weeks after the final challenge following long term challenges, whereas they returned to baseline within 2 weeks following short term challenges (data not shown). OVA challenges resulted in eosinophilia and lymphocytosis in BAL fluid, but with striking differences between protocols (Fig 3a, b). Short term challenges resulted in very strong eosinophilia accounting for 60–70% of total BAL cells and moderate lymphocytosis representing 9% of BAL cells. In contrast, long term challenges induced marked lymphocytosis accounting for 27% of BAL cells, accompanied by moderate eosinophilia of 24% of BAL cells. Following both challenge protocols BAL eosinophilia resolved after 2 weeks, while numbers of lymphocytes decreased over time but remained significantly elevated for 4 weeks after short term and for 8 weeks after long term challenges.


Reduced lung function in a chronic asthma model is associated with prolonged inflammation, but independent of peribronchial fibrosis.

Koerner-Rettberg C, Doths S, Stroet A, Schwarze J - PLoS ONE (2008)

Eosinophils and lymphocytes in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, numbers of (a) eosinophils, and (b) lymphocytes were determined in BAL fluid from 3 days to 8 weeks after final airway challenge, n≥12 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0,05, **/++ p<0,01, ***/+++ p<0,001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2215329&req=5

pone-0001575-g003: Eosinophils and lymphocytes in BAL fluid after long and short term airway challenges.Following OVA sensitisation and short or long term OVA challenges or after sham sensitisation and long or short term PBS challenges, numbers of (a) eosinophils, and (b) lymphocytes were determined in BAL fluid from 3 days to 8 weeks after final airway challenge, n≥12 per group from 5 independent experiments. Significant differences: * OVA challenges versus PBS controls, +long term versus short term OVA challenges, */+ p<0,05, **/++ p<0,01, ***/+++ p<0,001.
Mentions: To characterise the quality of airway inflammation, BAL cells were analysed. 72 hours after the final challenge total cell numbers in BAL fluid were raised 6–10 fold compared to control mice without significant differences between the two challenge protocols (PBS: 124,900±18,300 cells/ml, short term OVA: *1,081,100±244,900, long term OVA: *841,800±90,200, *p<0.05 versus PBS, n≥10). BAL cell numbers remained significantly elevated (3-fold over controls) until 8 weeks after the final challenge following long term challenges, whereas they returned to baseline within 2 weeks following short term challenges (data not shown). OVA challenges resulted in eosinophilia and lymphocytosis in BAL fluid, but with striking differences between protocols (Fig 3a, b). Short term challenges resulted in very strong eosinophilia accounting for 60–70% of total BAL cells and moderate lymphocytosis representing 9% of BAL cells. In contrast, long term challenges induced marked lymphocytosis accounting for 27% of BAL cells, accompanied by moderate eosinophilia of 24% of BAL cells. Following both challenge protocols BAL eosinophilia resolved after 2 weeks, while numbers of lymphocytes decreased over time but remained significantly elevated for 4 weeks after short term and for 8 weeks after long term challenges.

Bottom Line: Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response.In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

View Article: PubMed Central - PubMed

Affiliation: Children's Hospital, Ruhr University of Bochum, Bochum, Germany.

ABSTRACT

Background: In asthma, mechanisms contributing to chronicity remain to be determined. Recent models of sensitisation with prolonged airway allergen challenges reproduce typical features of chronic asthma. However, the interplay between inflammation, structural changes and lung function is poorly understood. This study was performed to delineate functional, structural and immunological airway changes after cessation of long term challenges to elucidate factors contributing to the development of prolonged lung function changes.

Methodology/principal findings: Mice sensitised systemically were consecutively challenged intranasally with ovalbumin for two or eight weeks. After the end of challenges, lung function, airway inflammation, features of airway remodelling, local T-cell cytokines and systemic ovalbumin-specific antibodies were monitored. Long term challenges resulted in airway hyperresponsiveness lasting 2 weeks and reduced baseline lung function for 6 weeks after their cessation. In contrast, these changes resolved within one week after short term challenges. Prolonged transforming growth factor beta (TGF-beta)1 production and marked peribronchial fibrosis were only induced by long term challenges. Importantly, fibrosis became apparent only after the onset of lung function changes and outlasted them. Further, long term challenges led to prolonged and intense airway inflammation with marked lymphocytosis, but moderate eosinophilia, sustained IL-5 production and ovalbumin-specific IgG2a antibodies, the latter suggesting a Th1 component to the immune response. In contrast, following short term challenges airway inflammation was dominated by eosinophils and associated with a strong, but transient IL-13 response.

Conclusions: Prolonged lung function changes after long term allergen challenges seem to develop and resolve independently of the persistent peribronchial fibrosis. They are more closely associated with intense airway inflammation, marked lymphocytosis, prolonged IL-5 and TGF-beta1 production in the airways and a Th1 immune response.

Show MeSH
Related in: MedlinePlus